ARRDC3 Inhibits the Progression of Human Prostate Cancer Through ARRDC3-ITGβ4 Pathway

Background: Arrestin domain-containing protein 3 (ARRDC3) is a member of the mammalian α-arrestins family, which has been identified as a tumor suppressor gene in human breast cancer, but its functions are still not clear in human prostate cancer (PCa). Objective: The purpose of the present study was to investigate clinical significance, biological functions and underlying mechanisms of ARRDC3 deregulation in PCa. Method: Involvement of ARRDC3 deregulation in malignant phenotypes of PCa was demonstrated by clinical sample evaluation, microarray analysis, and in vitro and in vivo experiments. The mechanisms underlying its regulatory effect on tumor progression were determined. Results: Microarray analysis found that ARRDC3 low expression was significantly associated with high Gleason score in TMA, and the expression level of ARRDC3 was negatively correlated with Gleason score, metastasis and biochemical recurrence in online Taylor Dataset. As revealed by the dataset, Kaplan-Meier analyses revealed that the biochemical recurrence-free survival (BCR-free) time of PCa patients with ARRDC3 high expression was longer than those with ARRDC3 low expression. Additionally, both univariate and multivariate analyses showed that the downregulation of ARRDC3 was an independent prognostic marker for BCR-free survival of patients with PCa. In vitro studies revealed that ARRDC3 could inhibit proliferation, migration and invasion of PCa cell lines. In vivo studies proved that ARRDC3 over-expressing cells formed significantly larger tumor nodules and remarkably speeded up tumor xenografts growth compared with the controls. Moreover, immunohistochemical scores of Ki67 and MMP-9 were significantly lower than those of the control group. Finally, correlation analysis indicated that the expression of ARRDC3 was negatively correlated with ITGβ ;4 in clinical PCa tissues and cell lines. Conclusion: Our data revealed that ARRDC3 can serve as a tumor suppressor to inhibit PCa progression and an independent marker to predict the risk of biochemical recurrence and metastasis after radical resection of PCa.